D-CSS_Attach1_SOW_Testing_Compound.pdf

Statement of Work

Title of Project:

Testing of NCGC00846044 Compound in the SUGEN-Hypoxia Model of Pulmonary Hypertension

Statement of Need and Purpose:

The need is for testing services to assess NCGC00846044 in a SUGEN-Hypoxia model of pulmonary hypertension to assess fibrosis, heart compliance, and pulmonary function in mice, using humanized-RXFP1 mice.

Background Information and Objective:

The National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) focuses on getting more treatments to more patients more quickly. Several thousand genetic diseases affect humans, of which only about 500 have any treatment. A novel drug, device or other intervention can take about 14 years and $2 billion to develop, with a failure rate exceeding 95 percent. NCATS is directly addressing this problem by discovering new technologies and other approaches that could greatly accelerate the process of developing and deploying solutions that can be used by all translational researchers.

The NCATS Early Translation Branch (ETB) is tasked with identifying and developing novel small molecule leads against a wide spectrum of human disease targets, which it accomplishes by screening thousands of small molecules in collaboration with both intra-and extramural researchers. In pursuit of this goal, the Center has a strong internal transdisciplinary team of scientists who continually discover novel small molecules for application against a wide range of human diseases.

As an ongoing high priority project for ETB we are in need of testing NCGC00846044 in the mouse SUGEN- Hypoxia model of pulmonary hypertension. NCGC00846044 was developed through NIH Molecular Libraries Program that set out to discover, optimize, and assess biological activity of small molecules agonists of human relaxin receptor 1 (RXFP1). The natural peptide hormone relaxin targets the class B G-protein coupled receptor RXFP1 but has limited utility clinically because of a short half-life in vivo. Optimized compounds from this series are potent and highly selective RXFP1 agonists with similar efficacy as the natural hormone in functional assays. To further understand the effect of NCGC00846044 ETB is in need of studying NCGC00846044 in a hypertensive mouse model to assess RXFP1 agonist effects on fibrosis, heart compliance, and pulmonary function. The SUGEN-Hypoxia model of pulmonary hypertension is the established standard animal model for this biology and is predictive of human efficacy.

Period of Performance:

Twelve (12) months

Scope of Work:

General Requirements:

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the Statement of Work below:

ATTACHMENT 1

Specific Requirements:

ETB is need of very specific testing that meets the following requirements:

• Procuring and having access to 72 knock-in human-RXFP1 mice and sourcing breeding mice

• Be able to house mice for 90 days in 15 cages (21 days quarantine and 69 days mouse model)

• Do echocardiography in 36 mice

• Data analysis to assess fibrosis, heart compliance, and pulmonary function

• Provide invasive hemodynamic measurements for pulmonary hypertension in 72 mice

• Conduct histology, gene, and protein expression studies and provide data

Vendor is responsible for providing 72 mice, by procuring breeding knock-in human-RXFP1 mice, house and administer NCGC00846044 to mice, study effects of NCGC00846044 on fibrosis, heart compliance, and pulmonary function using echocardiography, invasive hemodynamic measurements, and histology, gene, and protein expression studies.

Level of Effort:

Not applicable.

Government Responsibilities:

NCATS will deliver the compound to the Contractor.

Delivery or Deliverables:

Resulting data will be included in a final report and received by NCATS within 18 weeks after the mice have been obtained.

Reporting Requirements:

Progress reports and meeting every 3-4 weeks between key personal at contractor site and NCATS. Reports will cover progress in dosing, efficacy readouts, exposure, metabolite formation, clinical chemistry and histology.

Other Considerations:

Travel:

No travel is required.

Key Personnel:

None specified.

Information System Security Plan:

The Contractor shall apply the basic safeguarding requirements and procedures for security controls to protect covered contractor information systems as well as other specific safeguarding requirements specified by Federal agencies and departments relating to covered contractor information systems generally.

Data Rights:

The Government retains unlimited rights in all data generated under this contract.

Section 508:

The Contractor shall comply with applicable Section 508 accessibility requirements:

https://ocio.nih.gov/ITGovPolicy/NIH508/Pages/Resources.aspx

Publications and Publicity:

There shall be no publication of the data, results, findings, or conclusions generated under this contract without prior approval from the Government.

Confidentiality of Information:

The contractor, including all its employees, consultants, and subcontractors, shall maintain confidentiality of all information generated under this project.